Field of the Invention
This invention relates to the treatment of depression and post traumatic stress disorder (PTSD).
Description of the Related Art
Chronic Pain, Central Sensitization, and Mood Disorders
An ongoing and pervasive problem in the medical community is treating patients with chronic pain syndromes. It is well recognized today that chronic pain is fundamentally different from acute pain, also referred to as nociceptive pain, that results from a mechanical, chemical, metabolic or inflammatory insult. Central sensitization is a newly recognized diagnostic entity that underlies a broad range of phenotypic syndromes, including various chronic pain and mood disorders. Central sensitization refers to an abnormal state of functioning of the neurons and circuitry of the central pain intensity, perception and modulation systems; due to synaptic, chemical, functional and/or structural changes, in which pain is no longer coupled, as acute nociceptive pain is, to particular peripheral stimuli. Instead, the central nervous system (CNS) initiates, maintains and contributes to the generation of pain hypersensitivity and perception even in the absence of a peripheral stimulus. See, for example, C J Woolf, “Central sensitization: Implications for the diagnosis and treatment of pain”, PAIN, v. 152, pp. S2-S15 (2011).
Chronic pain and central sensitization represent an overlapping constellation of diagnostic conditions and syndromes. This may explain why there remains a critical lack of effective medical interventions to treat chronic pain disorders. Traditional pharmaceutical approaches generally deal with a single involved pathway, which tends to yield less than ideal results and is often associated with significant toxicity. For example, the treatment options most commonly investigated to date consist of centrally acting drugs. These include ketamine, dextromethorphan, gabapentin, pregabalin, duloxetine, milnacipran, lamotrigine; and not all of these have reached human trials at this time. Each has demonstrated a poor therapeutic index in trials.
It has been noted that major depressive disorder (MDD) and chronic pain syndrome often present as co-morbid conditions: 30-60% of cases in one report (M J Bair et al., “Association of depression and anxiety alone and in combination with chronic musculoskeletal pain in primary care patients”, Psychosomatic Medicine, v. 70(8), pp. 890-897 (2008)). A recent review on this topic suggests that there may be a shared neurobiological basis of MDD, fibromyalgia, neuropathic pain, and other chronic pain syndromes (V Maletic et al., “Neurobiology of depression, fibromyalgia and neuropathic pain”, Frontiers in Bioscience, v. 14, pp. 5291-5338 (2009). Robert Post first proposed that ‘kindling’ and sensitization may have similar neurobiological underpinnings, such as neuroplastic changes and alterations in gene expression (R M Post, “Kindling and sensitization as models for affective episode recurrence, cyclicity, and tolerance phenomenon”, Neuroscience & Biobehavioral Reviews, v. 31(6), pp. 858-873 (2007)).
Depression and Post Traumatic Stress Disorder
Depression, as discussed here, represents two disorders: dysthymic disorder (DD), classified in the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, American Psychiatric Association, Washington D.C., 2000) under code 300.4 (see DSM-IV-TR at pages 345-348 and 376-381), and major depressive disorder (MDD), classified in the DSM-IV-TR under code 296.3x (see DSM-IV-TR at pages 349-356 for a description of major depressive episode and pages 369-376 for MDD). Diagnostic criteria for DD are, in summary, (1) a depressed mood for most of the day for more days than not for at least 2 years; (2) the presence, while depressed, of symptoms such as sleep disturbances, fatigue, and feelings of hopelessness; (3) no continuous period of more than 2 months during the 2 years without the symptoms in (1) and (2); and no major depressive episode present in the first 2 years of the disturbance (i.e. so that the disorder is not better accounted for by MDD); diagnostic criteria for MDD are, in summary, the presence of at least one major depressive episode (the presence of 5 or more symptoms including at least one of depressed mood and loss of interest or pleasure present during the same 2-week period, representing a change from previous functioning; the symptoms causing clinically significant distress or impairment, and not due to the effects of a substance, medical condition, or bereavement) not better accounted for by other conditions and lack of manic, mixed, or hypomanic episodes. As the DSM-IV-TR notes (page 374), DD and MDD are differentiated based on severity, chronicity, and persistence, and “the differential diagnosis between them is made particularly difficult by the fact that the two disorders share similar symptoms . . . ”. Depression is commonly pharmacologically treated with antidepressants (such as the selective serotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptake inhibitors (SNRIs), and norepinephrine/dopamine reuptake inhibitors (NDRIs)), and also with the atypical antidepressants, tricyclic antidepressants, or monoamine oxidase inhibitors (MAOIs), or other medications, generally if the SSRI/SNRI/NDRI antidepressants are unsuccessful.
Post traumatic stress disorder (PTSD) is an anxiety disorder characterized by the re-experiencing of an extremely traumatic event accompanied by symptoms of increased arousal and by the avoidance of stimuli associated with the trauma, classified in the DSM-IV-TR under code 309.81 (see DSM-IV-TR at pages 429 and 463-468). Diagnostic criteria for PTSD are, in summary, that (1) the person has been exposed to a traumatic event in which both the person experienced, witnessed, or was confronted with one or more events that involved actual or threatened death or serious injury or a threat to physical integrity and the person's response involved intense fear, helplessness, or horror; (2) the event is persistently re-experienced; (3) there is a persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma); and (4) there are persistent symptoms of increased arousal (not present before the trauma) indicated by at least two of (i) difficulty falling or staying asleep, (ii) irritability or outbursts of anger, (iii) difficulty concentrating, (iv) hypervigilance, and (v) exaggerated startle response. PTSD is commonly pharmacologically treated with antidepressants (such as the SSRIs and SNRIs) and anxiolytics, sometimes acutely treated with antipsychotics, and insomnia and nightmares are sometimes treated with prazosin (an adrenergic α-blocker).
The usual pharmacological treatments for depression and PTSD are associated with a number of side effects, in particular the sexual side effects known with SSRIs and SNRIs, that may make them unattractive options for persons suffering from these disorders.
Pain Transmission and G-Protein Coupled Receptors
Pain transmission and modulation through the central nervous system network of neurons and support glial cells (microglia and astrocytes) is largely under the control of a large family of cellular receptors known as G-protein-coupled receptors (GPCRs). The function of these complex transmembrane receptors is to transduce extracellular stimuli into intracellular signaling including gene transcription. GPCRs modulate and/or mediate virtually all physiologic processes in eukaryotic organisms, including acute and chronic pain. An estimated 90% of all known GPCRs are expressed in the central nervous system. 80% of the currently proposed GPCR families have a known role in modulation of pain. Similarly, most of the identified genes associated with pain modulation are GPCR related genes (LS Stone et al., “In search of analgesia: Emerging role of GPCRs in pain”, Molecular Interventions, v. 9(5), pp. 234-241 (2009)).
In the pharmaceutical development industry, the search for new analgesic and mood modulating targets has its foundation in establishing central nervous system receptor groups for which ligands can be identified, leading to the manufacture of pharmaceutical compounds to provide pain relief and mood improvement. Regarding analgesia, there are for example, several recognized GPCR sub-groups that have been established as templates for drug development. Opioid receptors, cannabinoid receptors, GABA receptors, and α2 adrenergic receptors are examples of such established receptors for analgesic drug development.
Human Chorionic Gonadotropin (hCG) and the LH/hCG Receptor
Human chorionic gonadotropin (hCG) is a is a hormone produced during pregnancy that is made by the developing placenta after conception, and later by the placental component syncytiotrophoblast. hCG shares a receptor with Luteinizing Hormone (LH), the LH/hCG receptor. This receptor is a GPCR. Both hormones are produced in the same cells in the pituitary gland. Both LH and hCG are produced continually throughout life in males and females.
hCG is now recognized to have pleiotropic actions throughout the body as evidenced by the documented presence of receptors for hCG in multiple cellular compartments including the central nervous system (CNS). See C V Rao, “An overview of the past, present, and future of non-gonadal LH/hCG actions in reproductive biology and medicine”, Seminars in Reproductive Medicine, v. 19, pp. 7-17 (2001), and Z M Lei et al., “Neural actions of luteinizing hormone and human chorionic gonadotropin”. Seminars in Reproductive Medicine, v. 19, pp. 103-109 (2001).
In the adult CNS, hCG receptors have been established to be present in the hippocampal formation, hypothalamus, cerebral cortex, brain stem, cerebellum, pituitary gland, neural retina, spinal cord and the ependymal region (Z M Lei et al., “Novel expression of human chorionic gonadotropin/luteinizing hormone receptor gene in brain”, Endocrinology, v. 132, pp. 2262-2270 (1993). Both neurons and glial cells are shown to express receptors for hCG (Z M Lei et al., previously cited). It has been postulated that hCG may play an important signaling role in differentiation and development of tissue subsets from germ cell layering during the blastocyst stage (M J Gallego et al., “The Pregnancy Hormones HCG and Progesterone Induce Human Embryonic Stem Cell Proliferation and Differentiation into Neuroectodermal Rosettes”, Stem Cell Research and Therapy, v. 1, p. 28 (2010)) to organ development during fetal life (M A Abdallah et al., “Human Fetal Non-Gonadal Tissues Contain HCG/LH Receptors”, Journal of Clinical Endocrinology and Metabolism, v. 89, pp. 952-956 (2004)) and perhaps on some more subtle, yet clinically significant way, in adults. Recent evidence confirms the presence of hCG receptors in the adult CNS, and additional evidence supports hCG as a signaling hormone for tissue differentiation and growth. See C V Rao et al., “The past, present and future of non-gonadal LH/hCG actions in reproductive biology and medicine”, Molecular and Cellular Endocrinology, v. 269(1-2), pp. 2-8 (2007).
As noted above, the luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptor is a GPCR (LS Stone et al., previously cited). It has been specifically shown to complex with the Gai/o group resulting in modulation of neurotransmission (L Hu et al., “Essential role of G protein-gated inwardly rectifying potassium channels in gonadotropin-induced regulation of GnRH neuronal firing and pulsatile neurosecretion”, Journal of Biological Chemistry, v. 281(35), pp. 25231-25240 (2006)). Gai/o proteins mediate the widespread inhibitory effects of many neurotransmitters and they mediate the effects of almost all analgesic GCPR agonists (L S Stone et al., previously cited). D. Puett et al., “Structure-Function Relationships of the Luteinizing Hormone Receptor”, Annals of the New York Academy of Science, v. 1061, pp. 41-54 (2005), describe the LH/hCG receptor (which they refer to as the luteinizing hormone receptor) and studies on elucidating the mechanisms by which LH and hCG bind to it and activate it. They also describing transfected cells containing both wild-type and mutated LH/hCG receptors, and a single chain hCG-LH/hCG receptor complex containing a fusion protein of the two subunits of hCG linked to the LH/hCG receptor. X-L Meng et al., “Human Chorionic Gonadotropin Induces Neuronal Differentiation of PC12 Cells through Activation of Stably Expressed Lutropin/Choriogonadotropin Receptor”, Endocrinology, v. 148(12), pp. 5865-5873 (2007), describe the transfection of the LH/hCG receptor into PC12 cells (a cell line extensively used for studying neuronal differentiation) that then stably express the receptor, and studies in those cells when treated with hCG or LH and optional inhibitors. Various techniques for evaluating the interaction between the LH and hCG ligands and the PC12 cells are described.
Pain Management with hCG
In a series of applications including U.S. Provisional Application No. 61/475,908, filed 15 Apr. 2011; U.S. application Ser. No. 13/211,101, filed 16 Aug. 2011; and U.S. application Ser. No. 13/311,250, “Methods for Chronic Pain Management and Treatment Using hCG”, filed 5 Dec. 2011, there are described methods, etc. for the treatment of chronic pain or other central sensitization sequelae by the administration of hCG or its analogs or metabolites at doses equivalent to the subcutaneous administration of hCG at 50-200 IU/day, and 120-170 IU/day, preferably 140-160 IU/day.
The applications report that patients discontinued other analgesic agents and manifested a continued and improved analgesic response, confirming that another receptor group was indeed engaged to create the clinical response noted in that series. For example, the sedation, tolerance (requiring higher dosing for effect), constipation and addiction potential seen with chronic opiate administration was not seen in patients discontinuing opiate administration in favor of continued hCG administration, implying a different mechanism of action at a different analgesic receptor site for these patients.
The applications also suggest that hCG acts similarly on neural pathways involved in MDD that are subject to a very similar sensitization or ‘kindling’ phenomenon (implying that each episode of depression makes subsequent depressive episodes more likely and less dependent upon an external stimulus such as stress or sickness), where cellular structure and function are modulated and modified through many of the same CNS synaptic, cell signaling and transcriptional pathways, to effect depression.
The disclosures of the documents referred to in this application are incorporated into this application by reference.